Whether or not a virus infection is successfully controlled by the host or causes notable tissue damage in some or all individuals is a clinically relevant issue that lacks full understanding. In some instances, injury is a direct consequence of virus replication, but more commonly the host response to the virus accounts for much or even the majority of the tissue damage. This can be extensive and prolonged if the infection is difficult to control. Many viral and host factors influence the balance of events that culminate in immunity or pathology. In circumstances where viruses do cause exuberant tissue damage, it is important to identify the mechanisms that account for the injury that occurs and develop ways to counteract the problem. With chronic tissue damaging virus infections there is more need for therapeutic vaccines and immunomodulation therapy that can redirect established response patterns so that the tissue wounding is minimized and immunity restored. To achieve this latter objective, we hypothesize that finding a practical approach to expand the number and functions of regulatory T cells in vivo will represent a valuable means to counteract chronic inflammatory reactions caused by viruses. We choose this objective because past studies by many groups, including ourselves supported by this grant, have established that regulatory T cells of various types play a beneficial role to limit tissue damage during immune inflammatory reactions to self or extrinsic antigens that include viruses.
The aims of this proposal are to evaluate procedures that will expand and activate regulatory T cells (Treg) so that the severity and duration of viral induced immunopathological lesions can be controlled. The model we shall use is a blinding immunoinflammatory lesion in the cornea of the eye that results from ocular infection with the herpes simplex virus (HSV). The disease is referred as to as stromal keratitis (SK). The experimental mouse model reflects a similar lesion caused by HSV in the human eye and which is a significant cause of blindness. Prior studies had demonstrated that the lesion severity of SK in the mouse model was influenced by FoxP3+T cells, although how or where the Treg exert their beneficial influence remains uncertain. Experiments are planned to verify the protective role of Treg at various stages of SK pathogenesis and to evaluate if the Treg that influence events during SK need to be antigen specific or not. We shall also evaluate the hypothesis that enhancing the number and function of Treg represents a valuable means of therapy that could ultimately translate to the clinic. Treg expansion will be achieved by causing conventional naove or pre-committed non-regulatory T cells to convert to become FoxP3+ and regulatory in function. This objective is supported by published and preliminary data, but the approach has not been optimized, nor have additional strategies been used that expand the converted population and cause the converted Treg to sustain their regulatory function. Experiments will be pursued to achieve the latter objectives by combining the antigen stimulation and FTY720 drug treatment that causes Treg conversion with additional maneuvers that expand Treg and stabilize their converted phenotype. Past and ongoing studies also documented that galectin-1 and galectin-9 play a significant role in modulating the expression of viral induced immunoinflammatory lesions acting at least in part by affecting Treg numbers and function. Experiments are planned to further define how galectins 1 and 9 act in vivo and might be used therapeutically to diminish the consequences of HSV induced tissue damage.
The specific aims are 1 To demonstrate at which stage in SK pathogenesis Treg manipulation will influence the expression of virus induced immunopathology. 2 To develop procedures that can convert and expand uncommitted T cells to become Foxp3+Treg and show the value of this to inhibit viral induced immunoinflammatory lesions. 3 To further define the participation of galectins during the pathogenesis of SK and to determine how endogenously produced and exogenously administered galectins 1 and 9 act to modulate lesion severity. Key words immunity;immunopathology: regulatory T cells;herpes simplex virus;Stromal keratitis;galectins

Public Health Relevance

This project is designed to explore potential clinically useful approaches that will cause the body to expand and activate a subset of T lymphocytes that will act to diminish the pathological consequences of chronic tissue damaging virus infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense (IHD)
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Challberg, Mark D
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University of Tennessee Knoxville
Schools of Veterinary Medicine
United States
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Varanasi, Siva Karthik; Reddy, Pradeep B J; Bhela, Siddheshvar et al. (2017) Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function. J Virol 91:
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Rajasagi, Naveen K; Rouse, Barry T (2016) IL-2 complex treatment amplifies CD8+ T cell mediated immunity following herpes simplex virus-1 infection. Microbes Infect 18:735-746
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Reddy, Pradeep B J; Sehrawat, Sharvan; Suryawanshi, Amol et al. (2014) An approach to control relapse of inflammatory lesions after discontinuation of primary therapy. PLoS One 9:e98051
Sharma, Shalini; Rajasagi, Naveen K; Veiga-Parga, Tamara et al. (2014) Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection. Microbes Infect 16:648-60
Veiga-Parga, Tamara; Giménez, Fernanda; Mulik, Sachin et al. (2013) Controlling herpetic stromal keratitis by modulating lymphotoxin-alpha-mediated inflammatory pathways. Microbes Infect 15:677-87
Gimenez, Fernanda; Suryawanshi, Amol; Rouse, Barry T (2013) Pathogenesis of herpes stromal keratitis--a focus on corneal neovascularization. Prog Retin Eye Res 33:1-9
Veiga-Parga, Tamara; Sehrawat, Sharvan; Rouse, Barry T (2013) Role of regulatory T cells during virus infection. Immunol Rev 255:182-96
Veiga-Parga, Tamara; Suryawanshi, Amol; Mulik, Sachin et al. (2012) On the role of regulatory T cells during viral-induced inflammatory lesions. J Immunol 189:5924-33

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